CN105287627A - Unsaturated lactone ingredient and chemotherapy drug composition and application thereof - Google Patents
Unsaturated lactone ingredient and chemotherapy drug composition and application thereof Download PDFInfo
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- CN105287627A CN105287627A CN201510700188.5A CN201510700188A CN105287627A CN 105287627 A CN105287627 A CN 105287627A CN 201510700188 A CN201510700188 A CN 201510700188A CN 105287627 A CN105287627 A CN 105287627A
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Abstract
The invention discloses an unsaturated lactone ingredient and anti-tumor chemotherapy drug composition and medical application thereof. The invention provides unsaturated lactone ingredients extracted from natural plants, on the condition without obvious cytotoxicity dosage, these ingredients are combined with platinum chemotherapy drugs to have a collaborative anti-tumor effect and reverse a drug resistance effect of tumors to the platinum drugs.
Description
Technical field
The invention belongs to medical art, be specifically related to unsaturated lactone constituents and platinum-based chemotherapy pharmaceutical composition and medical usage thereof.
Background technology
Malignant tumor is the number one killer threatening human health, and caused 7,600,000 people's death (accounting for 13% of all death tolls) in 2008, the cancer mortality of about 70% occurs in low income and middle income country.Estimate that continuation is risen by whole world number of cancer deaths, will more than 1,310 ten thousand to the year two thousand thirty.
Chemotherapy is one of most important means of current clinical treatment malignant tumor, but causes Chemotherapy in Patients failure because tumor cell produces drug resistance to chemotherapeutics.Platinum-based chemotherapy medicine (cisplatin, carboplatin, oxaliplatin) is widely used in the treatment of various cancer, and its mechanism of anticancer action is studied clear not yet completely.At present, it is generally acknowledged that platinum medicine is combined by the DNA in cancerous cell, formed in chain, interchain links, affect the function of DNA, disturb DNA replication dna, transcribe, thus reach suppression, tumors destroyed.
The mechanism that tumor produces drug resistance to platinum class is very complicated, and the resistance mechanism found at present mainly contains following several respects: cisplatin is in the reduction of intracellular accumulation; The excessive inflow of thiol molecule such as GSH and passivation thereof all result in the drug resistance of cell to cisplatin; In DNA reparation approach, the excessive removing of cisplatin adduct also can cause the drug resistance to cisplatin; The false demonstration of the signal transduction pathway Function protein that control apoptotic pathways is relevant also can affect the sensitivity to cisplatin.Therefore, tumor, to the complexity of cisplatin resistance mechanism, is still " bottleneck " problem of research and development tumor drug resistance reversal agent so far.
At present, although some compounds show the reverse effect to tumor drug resistance, the toxic and side effects of these compounds limits its clinical application.Natural drug is low due to toxic and side effects, has the advantage of high-efficiency low-toxicity as tumor drug resistance reversal agent.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of unsaturated lactone constituents and platinum-based chemotherapy pharmaceutical composition and is preparing the application in Therapeutic cancer medicine.
Unsaturated lactone constituents exists in various plants medicine as feverfew Radix Inulae, Radix Vladimiriae, gray wool Radix Vladimiriae etc.Inventor isolates a series of unsaturated lactone compounds recently from the root of Radix Inulae (InulaheleniumL.), some compounds are under the dosage not having overt toxicity to cell, share with cisplatin the sensitivity adding cisplatin on drug resistant cell, this discovery is significant to platinum-based chemotherapy Drug-resistant to overcoming tumor.
Inventor compound and following similar in isolated unsaturated lactone from Radix Inulae, have the effect increasing cisplatin on drug resistant cellular sensitivity.
R
1, R
2and R
3be selected from hydrogen atom, hydroxyl, acyloxy, alkoxyl, halogen, amino, acylamino-; C
2, C
3, C
4, C
5, C
6, C
7, C
8, C
9, C
10, C
1between link form be singly-bound or double bond or epoxy bond; C
4, C
15between and C
10, C
14between link form be singly-bound or double bond or epoxy bond; C
5with C
10between be singly-bound or fracture mode; C
1with C
5between be fracture mode or singly-bound link.
Compositions provided by the invention, comprises the unsaturated lactone constituents shown in general formula (1) and platinum-based chemotherapy medicine, and wherein unsaturated lactone constituents and platinum-based chemotherapy medicine molar concentration ratio are 10:1 ~ 1:50.
Described platinum-based chemotherapy medicine is cisplatin, carboplatin or oxaliplatin.
Pharmaceutical composition of the present invention, also comprise optional pharmaceutically can the mixing of diluent, carrier, excipient, adjuvant or vehicle.
Pharmaceutical composition of the present invention, preferably, when R1, R2 and R3 in logical formula I are hydrogen atom, C
5with C
6between when being double bond, logical compound representated by formula I is alantolactone;
As R in logical formula I
1, R
2and R
3for hydrogen atom, C
4with C
15between when being double bond, logical compound representated by formula I is isoalantolactone.
The present invention also provides the purposes of described pharmaceutical composition in the medicine preparing Tumor suppression growth.Preferably, described tumor is ovarian cancer, hepatocarcinoma, gastric cancer, uterus carcinoma, pulmonary carcinoma, colorectal carcinoma, cancer of pancreas, renal carcinoma, esophageal carcinoma, skin carcinoma, carcinoma of prostate or leukemia.
Accompanying drawing explanation
Fig. 1. alantolactone and isoalantolactone and cisplatin share the inhibitory action to ovarian cancer cell growth.
Fig. 2 .Hoechst staining examine alantolactone and isoalantolactone and cisplatin share the effect of inducing ovarian cancer cell-apoptosis.
Fig. 3. alantolactone and isoalantolactone and cisplatin share the inhibitory action to liver cancer cell growth.
Detailed description of the invention
Below by specific embodiment, the present invention will be described, but these specific embodiments not should be understood to limitation of the present invention, alantolactone and isoalantolactone are several examples that inventor obtains, and the general formula compound (I) with these compounds with similar structures also has synergism with Cisplatin.
Embodiment 1:
After Radix Inulae pulverizing medicinal materials, with 95% ethanol extraction 3 times, reclaim ethanol, after gained extractum adds suitable quantity of water suspendible, with petroleum ether extraction 5 times, reclaim petroleum ether, obtain petroleum ether extract.
Pillar layer separation: petroleum ether extract is separated through silica gel column chromatography, eluting with petroleum ether-ethyl acetate, obtain alantolactone and isoalantolactone.
Embodiment 2:
Compound alantolactone and isoalantolactone and cisplatin share the inhibitory action to ovarian cancer cell growth.
To take the logarithm the OVCAR-3 cell of trophophase, add 96 orifice plates, every hole 9 × 10
3individual cell, cultivated after 24 hours, by alantolactone and isoalantolactone and variable concentrations Cisplatin, after effect 24h, every hole adds 20 μ LMTT (5mg/mL) solution, continues to cultivate 4h, remove supernatant, every hole adds 100 μ LDMSO, measures OD value by microplate reader at 570nm.The synergy of alantolactone and isoalantolactone and cisplatin (30 μMs) coupling is shown in Fig. 1.
Embodiment 3:
Alantolactone and isoalantolactone and cisplatin share the effect of inducing ovarian cancer cell-apoptosis.
To take the logarithm the OVCAR-3 cell of trophophase, add 6 orifice plates, treat that cell density is 70%, add drug treating 24h, remove culture medium, with the attached cell in the careful rinse hole of PBS 2 times, residual media is cleaned, and does not lose attached cell as far as possible.After rinse completes, be placed in superclean bench and naturally dry.Add freshly prepared cell fixative (methanol: glacial acetic acid=3:1 (v/v)), every hole adds 500 μ L, and room temperature is removed fixative, naturally dried after placing 10min.Add freshly prepared Hoechst dyeing liquor (5 μ g/mL) to dye, every hole adds 300 μ L, and after lucifuge dyeing 45min, remove Hoechst dyeing liquor, wash away remaining dyeing liquor with PBS, lucifuge, dries naturally.Under being placed in fluorescence inverted microscope, with 340nm ultraviolet excitation, observation of cell nuclear morphology changes, and Taking Pictures recording.Nuclei dyeing chromaticness is assembled or is formed apoptotic body.The results are shown in Figure 2.As can be seen from Figure 3, after alantolactone and isoalantolactone and cisplatin share, apoptotic cell showed increased.
Embodiment 4:
Alantolactone and isoalantolactone and cisplatin share the impact on Morphology of Hepatocellular Carcinoma.
The human liver cancer cell SK-HEP-1 of trophophase of taking the logarithm adds 96 orifice plates, every hole 5 × 10
3individual cell, cultivate after 24 hours, with 0.5%DMSO process cell for contrast, with alantolactone, isoalantolactone, variable concentrations cisplatin and synergy cell 24h, every hole adds 20 μ LMTT (5mg/mL) solution, continues to cultivate 4h, removes supernatant, every hole adds 100 μ LDMSO, measures OD value by microplate reader at 570nm.The synergy that compound and cisplatin (20 μMs) share is shown in Fig. 3.
Claims (7)
1. a pharmaceutical composition, comprises the unsaturated lactone compounds shown in following formula and platinum-based chemotherapy medicine, and wherein unsaturated lactone compounds and platinum-based chemotherapy medicine molar concentration ratio are 10:1 ~ 1:50,
R
1, R
2and R
3be selected from hydrogen atom, hydroxyl, acyloxy, alkoxyl, halogen, amino, acylamino-respectively; C
2, C
3, C
4, C
5, C
6, C
7, C
8, C
9, C
10, C
1between link form be singly-bound or double bond or epoxy bond; C
4, C
15between and C
10, C
14between link form be singly-bound or double bond or epoxy bond; C
5with C
10between be singly-bound or fracture mode; C
1with C
5between be fracture mode or singly-bound link.
2. pharmaceutical composition according to claim 1, is characterized in that, described platinum-based chemotherapy medicine is cisplatin, carboplatin or oxaliplatin.
3. pharmaceutical composition according to claim 1, is characterized in that, also comprise optional pharmaceutically can diluent, carrier, excipient, adjuvant or vehicle.
4. pharmaceutical composition according to claim 1, is characterized in that, described unsaturated lactone compounds is alantolactone.
5. pharmaceutical composition according to claim 1, is characterized in that, described unsaturated lactone compounds is isoalantolactone.
6. the purposes of the pharmaceutical composition described in any one of Claims 1 to 5 in the medicine preparing Tumor suppression growth.
7. purposes according to claim 6, is characterized in that, described tumor is ovarian cancer, hepatocarcinoma, gastric cancer, uterus carcinoma, pulmonary carcinoma, colorectal carcinoma, cancer of pancreas, renal carcinoma, esophageal carcinoma, skin carcinoma, carcinoma of prostate or leukemia.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510700188.5A CN105287627A (en) | 2015-10-23 | 2015-10-23 | Unsaturated lactone ingredient and chemotherapy drug composition and application thereof |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866955A (en) * | 2017-01-16 | 2017-06-20 | 石家庄学院 | A kind of isoalantolactone derivative containing polyethylene glycol groups and its preparation and application |
| CN107445931A (en) * | 2016-05-30 | 2017-12-08 | 天津尚德药缘科技股份有限公司 | Alantolactone derivative, its pharmaceutical composition and its production and use |
| CN112920147A (en) * | 2021-01-29 | 2021-06-08 | 武汉大学 | Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs |
| CN112920146A (en) * | 2021-01-29 | 2021-06-08 | 武汉大学 | Sesquiterpenoids, preparation method thereof and application thereof in preparing anti-inflammatory drugs |
| CN113521061A (en) * | 2021-08-17 | 2021-10-22 | 张茗涵 | Application of traditional Chinese medicine costustoot extract in preparation of medicine for treating pediatric tumors |
Citations (1)
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| KR20150101393A (en) * | 2014-02-25 | 2015-09-03 | 서울대학교산학협력단 | The pharmaceutical composition inula helenium hexane fractions thereof or compound isolated from the fraction comprising inhibitory activity of stat3 for prevention or treatment of breast cancer |
-
2015
- 2015-10-23 CN CN201510700188.5A patent/CN105287627A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150101393A (en) * | 2014-02-25 | 2015-09-03 | 서울대학교산학협력단 | The pharmaceutical composition inula helenium hexane fractions thereof or compound isolated from the fraction comprising inhibitory activity of stat3 for prevention or treatment of breast cancer |
Non-Patent Citations (3)
| Title |
|---|
| DAVID C. DORN ET AL.: "Tumor cell specific toxicity of Inula helenium extracts", 《PHYTOTHERAPY RESEARCH》 * |
| YEONG-IN YANG ET AL.: "Costunolide induces apoptosis in platinum-resistant human ovarian cancer cells by generating reactive oxygen species", 《GYNECOLOGIC ONCOLOGY》 * |
| 王美德等: "《现代护理学辞典》", 31 March 1992 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107445931A (en) * | 2016-05-30 | 2017-12-08 | 天津尚德药缘科技股份有限公司 | Alantolactone derivative, its pharmaceutical composition and its production and use |
| CN106866955A (en) * | 2017-01-16 | 2017-06-20 | 石家庄学院 | A kind of isoalantolactone derivative containing polyethylene glycol groups and its preparation and application |
| CN106866955B (en) * | 2017-01-16 | 2019-07-30 | 石家庄学院 | A kind of isoalantolactone derivative containing polyethylene glycol groups and its preparation and application |
| CN112920147A (en) * | 2021-01-29 | 2021-06-08 | 武汉大学 | Sesquiterpenoids, preparation method thereof and application thereof in preparing antitumor drugs |
| CN112920146A (en) * | 2021-01-29 | 2021-06-08 | 武汉大学 | Sesquiterpenoids, preparation method thereof and application thereof in preparing anti-inflammatory drugs |
| CN113521061A (en) * | 2021-08-17 | 2021-10-22 | 张茗涵 | Application of traditional Chinese medicine costustoot extract in preparation of medicine for treating pediatric tumors |
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Application publication date: 20160203 |